This project was designed to develop models for studying the mechanism of contraceptive action of Zona Pellucida (ZP) antigens and autoimmune ovarian failure. In the preliminary study, a peptide based on the sequence of human ZP3 was found to be immunogenic in macaques, eliciting peptide-reactive T cells and antibodies that bound to macaque ZP in situ. Immunization had no effect on ovarian cycles or morphology, but appeared to induce infertility. It has since been found that the distribution and subpopulations of T cells in the ovaries of macaques were not affected by immunization with the peptide. Four peptide constructs based on the sequence of cynomolgus macaque ZP3 have now been tested in mice. The monomeric peptide (P1) was not immunogenic unless it was conjugated to a carrier, but three multiple antigen peptides (maps; multiple peptides on a branched lysine core) were immunogenic without a carrier protein, inducing both antibody and T cell responses. P1 conjugated to tetanus toxoid (P1-TT) and a hybrid map with the B cell epitope of P1 and a T cell epitope from tetanus toxoid were tested for immunogenicity in two cynomolgus macaques each. P1-TT was found to be considerably more immunogenic than the hybrid map in macaques, although the two constructs produced approximately equivalent anti-P1 titers in mice. Therefore, P1-TT was chosen for immunization of 12 female cynomolgus macaques prescreened for normal ovarian cyclicity and previous pregnancies. A matched panel of antibody titers has revealed that the primary response of the females to P1 is surprisingly strong two weeks after the primary immunization. When serum titers have reached a plateau, the fertility of the females will be assessed. The immunogenicity of the self-peptide P1 suggests that peptide antigens based on the ZP are promising candidates for a contraceptive vaccine.